Recent insights into how aggressive cancer cells proliferate and propagate the disease

Not all cancer metastases have the identical destructive effect. Researchers reveal different mechanisms in experiments.

A recent paper in “Cell Reports”, co-led by Dr. Christina Scheel from the Skin Cancer Center on the Ruhr University Bochum, Germany, presents recent mechanistic insights into how essentially the most aggressive cancer cells proliferate and propagate the disease. The work was initiated during Dr. Scheel’s tenure on the Helmholtz Center Munich and represents the fruits of a collaborative effort with researchers from German Cancer Center Heidelberg and ETH Zurich. The study was published within the journal Cell reports on May 30, 2023.

For many forms of cancer, the first tumor isn’t the reason behind death, but metastasis, the dissemination of cancer cells throughout the body. Metastatic progression is a fancy cascade of steps, and there is usually a significant delay between the initial spread and subsequent growth, eventually destroying vital organs, equivalent to the lung, liver or brain. Researchers from the Skin Cancer Center at Ruhr University Bochum, the Helmholtz Center Munich, the German Cancer Center Heidelberg and the ETH Zurich have studied the properties of metastatic breast cancer cells by directly analyzing metastatic biopsies from patients.

Cells change their identity

They initially focused on the activation of a cellular program that has long been implicated in metastasis, the Epithelial-Mesenchymal Transition (EMT). In experimental settings, the activation of this program has been shown to vary the identity of cancer cells, equivalent to breast or certain forms of skin cancer, thereby rendering these epithelial cancer cells more motile through the adoption of properties of mesenchymal cells, equivalent to fibroblasts. Importantly, the researchers discovered that each epithelial and mesenchymal cancer cells were present in metastatic biopsies. Nevertheless, only the epithelial cells propagated the disease and initiated recent metastases in experimental models.

There are still conflicting data on the precise role of EMT in metastasis. We predict our discovery has the potential to unify a lot of them by describing a brand new mechanism at play.”

Dr. Christina Scheel, one among the senior authors

Specifically, the researchers then employed a series of molecular analyses to find a worldwide epigenetic program in breast cancer cells that determined whether these cells were capable of hold on to their epithelial identity upon activation of EMT or change into completely reprogrammed to a mesenchymal cell state. The latter process was related to lack of growth potential. Finally, the authors describe that the interplay between two proteins, the transcription aspects ZEB1 and GRHL2 determined which route breast cancer cells take upon activation of EMT. Thereby, this work reveals on the molecular level how cancer cells employ plasticity, the power to vary fundamental properties, to adopt properties that promote metastatic growth. In the longer term, it would be highly interesting to find out to which extent these observations will be transferred to other epithelial cancers and in addition, whether these insights will be used to therapeutically goal essentially the most aggressive cancer cells.